Gene networks controlling the complex, hormonally-regulated growth and development of the mammary gland are likely to involve the same genes which, aberrantly expressed, contribute to the onset of breast cancer and its progression to metastasis. The overall goal of this Program Project is thus to identify and characterize these gene pathways, in order to define inclusive expression patterns that accurately predict the likelihood of clinical recurrence so that patients can be selected to receive or be spared adjuvant therapy. Several novel gene networks which we have found to have roles in normal mammary development and progression to cancer will be explored in terms of their interactions and their potential as targets for treatment and prevention, and we will seek to integrate comprehensive gene amplification and expression information combining two molecular profiling approaches. The individual projects are: 1) integrating RNA expression and array CGH profiles to predict long-term breast cancer progression, using a unique collection of frozen tumor specimens with >12 years clinical follow-up to identify individual gene pathways and comprehensive molecular signatures indicating the metastatic capability of an individual patient's tumor; 2) defining the tumor suppressor role of the SAFB scaffold attachment factors, whose genetic locus we have found to show the highest loss of heterozygosity yet reported in breast cancer; 3) targeting IGF-I and its cross-talk with the estrogen pathway in progression to malignancy, based on our findings and others that activation of IGF system components is prognostically ominous, that serum IGF-I is a breast cancer risk factor, and that there is direct positive feedback between the IGF and estrogen systems; 4) determining the role of the Ptc1 hedgehog receptor in mammary ductal development and progression to neoplasia, since we find that aberrant Ptc1 leads to ductal hyperplasia and that the hedgehog network regulates functions likely to be critical for metastatic behavior; 5) investigate the role of p190-B RhoGAP interactions in mammary development, particularly the invasive growth of the terminal end bud into the mammary fat pad, and also in breast cancer invasion and metastasis. These Projects will be supported by a Pathology and Tissue Resource, a Biostatistics and Array Analysis Core, and Animal Handling and Imaging Core. These highly interactive projects are designed to enhance our knowledge of how mammary development can become malignant and invasive, and to define gene amplification and expression profiles which will select those breast cancer patients who may truly benefit from adjuvant therapy.